The present invention relates to a novel process for the preparation of tricyclic amino-alcohol derivatives or salts thereof which are useful for treating and preventing diabetes, obesity, hyperlipidemia and the like and have the formula (1): 
wherein
R1 represents a lower alkyl group or a benzyl group;
*1 represents an asymmetric carbon atom;
R2 represents a hydrogen atom, a halogen atom or a hydroxyl group; and
A represents one of the following groups: 
xe2x80x83wherein X represents NH, O or S; R6 represents a hydrogen atom, a hydroxyl group, an amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R6 is not a hydrogen atom. This invention also relates to intermediates useful for the preparing process.
JP-A-9-249623 (WO 97/25311) and WO 99/01431 describe in detail processes for the preparation of the compounds of the above-mentioned general formula (1) and also describe that these compounds are very useful for treating and preventing diabetes, obesity, hyperlipidemia and the like.
Problems to be Solved
However, the study of the above known processes carried out by the present inventors showed that the said processes were not necessarily a practical process. There has been a need for a convenient, practical preparing process with low cost which comprises a small number of steps with good industrial work efficiency.
Means to Solve the Problems
The study carried out by the present inventors showed some disadvantages involved in the conventional processes for preparing a compound of the formula (1) set forth above, wherein the disadvantages were that the processes required many reaction steps and several purifying works such as chromatography, and did not necessarily provide a good yield. In addition, if an optical isomer, such as R-form of a compound of the formula (1) is to be finally obtained according to the synthesizing route disclosed in the above patent publications, the carbonyl group is reduced with borane as a reducing agent in the presence of a chiral auxiliary agent represented by the following general formula (15): 
This chiral auxiliary agent is very expensive and the process for the preparation thereof is very complicated. Moreover, the chiral auxiliary agent is a hazardous combustible substance and an asymmetric reduction using the said chiral auxiliary agent requires strictly anhydrous conditions, strict temperature controls, complicated works and the like, which will become problematic when the chiral auxiliary agent is industrially used.
In order to solve the above problems, the present inventors examined a variety of synthesizing processes. As a result, the present inventors have established preferred synthesizing processes successfully and completed the present invention.
That is, the aspect of the first synthesizing route of the present invention is a process for the preparation of a compound of the formula (1): 
wherein R1 represents a lower alkyl group or a benzyl group; R2 represents a hydrogen atom, a halogen atom or a hydroxyl group; *1 represents an asymmetric carbon atom; and A represents one of the following groups: 
wherein X represents NH, O or S; R6 represents a hydrogen atom, a hydroxyl group, an amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R6 is not a hydrogen atom, which comprises the following steps (a) to (c):
(a)
i) reacting a compound of the formula (4): 
xe2x80x83wherein R1 is as defined above; R21 represents a hydrogen atom, a halogen atom, a hydroxyl group or a protected hydroxyl group; R3 represents an amino-protecting group or a hydrogen atom, with a compound of the formula (12): 
xe2x80x83wherein R4 represents an amino-protecting group or a hydrogen atom; and Axe2x80x2 represents one of the following groups: 
xe2x80x83wherein X represents NH, O or S; R61 represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R61 is not a hydrogen atom, to give a compound of the formula (3): 
xe2x80x83wherein R1, R21, R3, R4 and Axe2x80x2 are as defined above; or
ii) coupling a compound of the formula (4) with a compound of the formula (14): 
xe2x80x83wherein R4 is as defined above, to give a compound of the formula (6): 
xe2x80x83wherein R1, R21, R3 and R4 are as defined above; or
iii) further converting the primary hydroxyl group of the compound of the formula (6) into a leaving group B3 to give a compound of the formula (5): 
xe2x80x83wherein R1, R21, R3 and R4 are as defined above, and B3 represents a leaving group; or
iv) further reacting the resulting compound of the formula (5) with a compound represented by Axe2x80x2xe2x80x94OH wherein Axe2x80x2 is as defined above to give a compound of the formula (3);
(b) then reducing the resulting compound of any one of the formulae (3), (5) and (6) to give a compound of the formula (2) as follows:
i) reducing the compound of the formula (3) to give an amino-alcohol of the formula (2): 
xe2x80x83wherein R1, R21, R3, R4 and Axe2x80x2 are as defined above, and *1 represents an asymmetric carbon atom; or
ii) reducing the compound of the formula (5) to give a compound of the formula (7): 
xe2x80x83wherein R1, R21, R3, R4 and B3 are as defined above, and *1 represents an asymmetric carbon atom, or
iii) reducing the compound of the formula (6) to give a compound of the formula (8): 
xe2x80x83wherein R1, R21, R3 and R4 are as defined above, and *1 represents an asymmetric carbon atom, and converting the primary hydroxyl group of the resulting compound of the formula (8) into a leaving group B3 to give a compound of the formula (7), then reacting the compound of the formula (7) obtained by either step as set forth above with a compound represented by Axe2x80x2xe2x80x94OH wherein Axe2x80x2 is as defined above to give an amino-alcohol of the formula (2); and
(c) simultaneously or sequentially removing the protecting groups of the compound of the formula (2) obtained by any one of processes as set forth above to give a compound of the formula (1).
The aspect of the first synthesizing route of the present invention is a process for the preparation of a compound of the above-mentioned general formula (1), which comprises the following steps (a) to (c):
(a) reacting a compound of the formula (4): 
xe2x80x83wherein R1 is as defined above; R21 represents a hydrogen atom, a halogen atom, a hydroxyl group or a protected hydroxyl group; R3 represents an amino-protecting group or a hydrogen atom, with a compound of the formula (12): 
xe2x80x83wherein R4 represents an amino-protecting group or a hydrogen atom; and Axe2x80x2 represents one of the following groups: 
xe2x80x83wherein X represents NH, O or S; R61 represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R61 is not a hydrogen atom, to give a compound of the formula (3): 
xe2x80x83wherein R1, R21, R3, R4 and Axe2x80x2 are as defined above;
(b) reducing the resulting compound of the formula (3) to give an amino-alcohol of the formula (2): 
xe2x80x83wherein R1, R21, R3, R4 and Axe2x80x2 are as defined above, and *1 represents an asymmetric carbon atom; and
(c) simultaneously or sequentially removing the protecting groups to give a compound of the formula (1).
In the aspect of the first synthesizing route set forth above, a compound represented by the formula (3) is the first preferred intermediate which is a novel compound and is relatively good in crystallinity. The said compound does not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
Specific examples of a compound represented by the formula (3) include:
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(3-methyl sulfonylamino)phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-[3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(4-benzyloxy-3-methylsulfonylamino)phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-[4-benzyloxy-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(4-chloro-3-methylsulfonylamino)phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-[4-chloro-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(4-bromo-3-methylsulfonylamino)phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-[4-bromo-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-[2-(6-benzyloxy-9H-carbazol-2-yloxy)]ethyl]amino-1-[3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-[2-(6-benzyloxy-9H-carbazol-2-yloxy)]ethyl]amino-1-[4-benzyloxy-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone; and
2-[N-benzyl-N-[2-(6-benzyloxy-9H-carbazol-2-yloxy)]ethyl]amino-1-(4-chloro-3-methylsulfonylamino)phenylethanone.
The said examples also include:
2-[N-benzyl-N-[2-(dibenzothiophene-3-yloxy)]ethyl]amino-1-(4-benzyloxy-3-methylsulfonylamino)phenylethanone; and
2-[N-benzyl-N-[2-(dibenzothiophene-3-yloxy)]ethyl]amino-1-[4-benzyloxy-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone.
In the steps set forth above, the step in which a compound of the formula (3) is reduced to give a compound of the formula (2) is a particularly characteristic of the present process.
In addition, when one of the optical isomers of a compound of the formula (1) is to be obtained in the steps set forth above, a compound of the formula (3) is preferably asymmetrically reduced. In this case, both of an amino-alcohol of the formula (2) and a compound of the formula (1) are obtained as one of their optical isomers, respectively. This is also characteristic of the present process.
Further, in the steps set forth above, the step in which a compound of the formula (4) is reacted with a compound of the formula (12) to give a compound of the formula (3) is also characteristic of the present process.
The aspect of the second synthesizing route of the present invention is a process for the preparation of a compound of the above-mentioned general formula (1), which comprises the following steps:
reacting a compound of the formula (4) with a compound of the formula (14): 
xe2x80x83wherein R4 is as defined above, to give a compound of the formula (6): 
xe2x80x83wherein R1, R21, R3 and R4 are as defined above; and
(i) converting the terminal hydroxyl group (the primary hydroxyl group) of the side-chain of the compound of the formula (6) into a leaving group B3 to give a compound of the formula (5): 
xe2x80x83wherein R1, R21, R3 and R4 are as defined above, and B3 represents a leaving group; and reacting the compound of the formula (5) with a compound represented by Axe2x80x2xe2x80x94OH wherein Axe2x80x2 is as defined above to give a compound of the formula (3); or
(ii) reacting the compound of the formula (6) with a compound represented by Axe2x80x2xe2x80x94OH according to Mitsunobu reaction to give a compound of the formula (3); and
then the compound of the formula (3), obtained by either step set forth above, is subjected to the sequential reaction steps as set forth above to give a compound of the formula (1) via a compound of the formula (2).
In the aspect of the second synthesizing route set forth above, a compound represented by the formula (18) including the formulae (6) and (5), is the second preferred intermediate which is a novel compound. The said compound does not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
Specific examples of a compound represented by the formula (6) include:
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[4-benzyloxy-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[4-chloro-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone; and
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[4-bromo-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone.
Further, examples of a compound represented by the formula (5) include:
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[4-benzyloxy-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone;
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[4-chloro-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone; and
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[4-bromo-3-(N-benzyl-N-methylsulfonylamino)]phenylethanone.
In the steps set forth above, the step in which a compound of the formula (4) is reacted with a compound of the formula (14) to give a compound of the formula (6) is also characteristic of the present process.
In the steps set forth above, the step in which a compound of the formula (6) is react with a compound represented by Axe2x80x2xe2x80x94OH according to Mitsunobu reaction to give a compound of the formula (3) is also characteristic of the present process.
The aspect of the third synthesizing route of the present invention is a process for the preparation of a compound of the above-mentioned general formula (1), which comprises the following steps:
reducing a compound of the formula (5) to give a compound of the formula (7): 
xe2x80x83wherein R1, R21, R3, R4, B3 and *1 are as defined above, which is then condensed with a compound represented by Axe2x80x2xe2x80x94OH to give an amino-alcohol of the formula (2). The amino-alcohol is subjected to the same reactions with those as set forth above to give a compound of the formula (1).
In this synthesizing route, the reduction of a compound of the formula (5) can be carried out by asymmetrically reducing method to give one of the optical isomers of a compound of the formula (7), which can be then subjected to the following steps to give one of the optical isomers of each compound of the formulae (2) and (1). These steps are characteristic of the present process.
In the aspect of the third synthesizing route set forth above, a compound of the formula (7), which is included within the formula (19), is novel and is the third preferred intermediate. The compound does not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
Specific examples of a compound represented by the formula (7) include:
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[3-(N-benzyl-N-methylsulfonylamino)]phenylethanol;
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[4-chloro-3-(N-benzyl-N-methylsulfonylamino)]phenylethanol;
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[4-bromo-3-(N-benzyl-N-methylsulfonylamino)]phenylethanol; and
2-[N-benzyl-N-(2-bromoethyl)]amino-1-[4-benzyloxy-3-(N-benzyl-N-methylsulfonylamino)]phenylethanol.
The aspect of the fourth synthesizing route of the present invention is a process for the preparation of a compound of the above-mentioned general formula (1), which comprises the following steps:
reducing a compound of the formula (6) to give a compound of the formula (8): 
xe2x80x83wherein R1, R21, R3, R4 and *1 are as defined above;
(i) converting the terminal hydroxyl group of the side-chain of the compound of the formula (8) into a leaving group B3 to give a compound of the above-mentioned general formula (7), which was then condensed with a compound represented by Axe2x80x2xe2x80x94OH to give a compound of the formula (2); or
(ii) reacting a compound of the formula (8) with a compound represented by Axe2x80x2xe2x80x94OH according to Mitsunobu reaction to give a compound of the formula (2); and
subjecting the compound of the formula (2), obtained by either step, to deprotecting treatment as set forth above to give the compound of the formula (1).
In this synthesizing route, the reduction of a compound of the formula (6) can be carried out by asymmetrically reducing method to give one of the optical isomers of a compound of the formula (8), which can be then subjected to the following steps to give one of the optical isomers of each compound of the formulae (7), (2) and (1). These steps are characteristic of the present process.
In the aspect of the fourth synthesizing route set forth above, a compound of the formula (8), which is included within the formula (19), is novel and is the third preferred intermediate. The compound does not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
Specific examples of a compound represented by the formula (8) include:
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[3-(N-benzyl-N-methylsulfonylamino)]phenylethanol;
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[4-benzyloxy-3-(N-benzyl-N-methylsulfonylamino)]phenylethanol;
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[4-chloro-3-(N-benzyl-N-methylsulfonylamino)]phenylethanol; and
2-[N-benzyl-N-(2-hydroxyethyl)]amino-1-[4-bromo-3-(N-benzyl-N-methylsulfonylamino)]phenylethanol.
In the aspect of the fourth synthesizing route set forth above, the step in which a compound of the formula (8) is react with a compound represented by Axe2x80x2xe2x80x94OH according to Mitsunobu reaction to give a compound of the formula (2) is characteristic of the present process and is preferred.
Furthermore, the aspect of the fifth synthesizing route of the present invention is a process for the preparation of a compound of the above-mentioned general formula (1), which comprises the following steps:
condensing a compound of the formula (4) with a compound of the formula (13): 
xe2x80x83wherein B1 and B2 may be the same or different and represent a halogen atom, to give a compound of the formula (11): 
xe2x80x83wherein R1, R21, R3 and B1 are as defined above;
reducing the compound of the formula (11) to give a compound of the formula (10): 
xe2x80x83wherein R1, R21, R3, B1 and *1 are as defined above, and protecting the amino group of which is then protected with an amino-protecting group R5, followed by condensing the compound with a compound represented by Axe2x80x2xe2x80x94OH to give a compound of the formula (9): 
xe2x80x83wherein R1, R21, R3, Axe2x80x2 and *1 are as defined above, and R5 represents an amino-protecting group; and
simultaneously or sequentially removing the protecting groups to give a compound of the formula (1).
In this synthesizing route, the reduction of a compound of the formula (11) can be carried out by asymmetrically reducing method to give one of the optical isomers of a compound of the formula (10), which can be then subjected to the following steps to give one of the optical isomers of each compound of the formulae (9) and (1). These steps are characteristic of the present process.
In the aspect of the fifth synthesizing route set forth above, a compound of the formula (11), which is included within the formula (18), and a compound of the formula (10), which is included within the formula (19), are novel and are the forth and fifth preferred intermediates. The compounds do not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
As used herein, xe2x80x9chalogen atomxe2x80x9d includes fluorine, chlorine, bromine and iodine, and among them, chlorine, bromine or iodine atom is generally preferred. Chlorine and bromine are particularly preferred.
R21 and R2 may be a hydrogen atom, a halogen atom or a hydroxyl group (R21 may also be a protected hydroxyl group), with hydrogen being particularly preferred. A halogen atom is also preferred as R21 and R2. The halogen atom may be fluorine, chlorine or bromine, with chlorine and bromine being particularly preferred.
The leaving groups B1 and B3 may be, for example, a halogen atom or a substituted sulfonyloxy group. The halogen atom includes chlorine, bromine and iodine. The substituted sulfonyloxy group includes methanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethane-sulfonyloxy and the like.
B2 is a halogen atom, with chlorine, bromine and iodine being generally preferred. Chlorine and bromine are particularly preferred.
The term xe2x80x9clower alkylxe2x80x9d means a straight or branched saturated hydrocarbon containing 1 to 6 carbon atoms and may be preferably a straight or branched alkyl group, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl and hexyl, or a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Methyl is particularly preferred.
R1 may be preferably the lower alkyl group as set forth above, with methyl being particularly preferred. A benzyl group may be also preferred as R1.
R3 and R4 may be a hydrogen atom and are preferably an amino-protecting group. Examples of the amino-protecting group include, for example, an acyl group, an acyloxy group and an easily removable aralkyl group. The easily removable aralkyl group may be benzyl, substituted benzyl, naphthyl or substituted naphthyl and the like, with benzyl being particularly preferred. The aralkyl group to be used may be, for example, an aralkyl group containing 7 to 16 carbon atoms. Specific examples thereof include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl)methyl, 2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl, wherein the phenyl or naphthyl moiety may have suitable substituents such as alkyl group, alkoxy group and halogen atom on suitable positions.
The amino-protecting group R5 may be, for example, an easily removable acyl or acyloxy group. The acyl or acyloxy group may be, for example, acetyl, haloacetyl, benzoyl, substituted benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, with tert-butoxycarbonyl being particularly preferred.
R61 and R6 in Axe2x80x2 and A may be a hydrogen atom, a hydroxyl group (in case of R61, a protected hydroxyl group), an amino group (in case of R61, a protected amino group) or an acetylamino group, with hydrogen being particularly preferred. In addition, a hydroxyl group (in case of R61, a protected hydroxyl group) may be also preferred. *2 represents an asymmetric carbon atom and a compound containing *2 may be an optically active or racemic compound.
A carbazole group is particularly preferred as A.
Each compound of the formulae (1), (2), (7), (8), (9) and (10), in which formulae *1 means an asymmetric carbon atom, can be in the form of two optical isomers. Therefore, not only optically pure isomers of the said compounds, but also a mixture of any two isomers are encompassed in the present invention. From the viewpoint of pharmacological activity, a preferred configuration of the asymmetric carbon may be the absolute configuration R.
The hydroxyl-protecting group is not limited as long as it is commonly used as a hydroxyl-protecting group. Preferred examples of easily and selectively removable protecting group generally include, for example, a trialkylsilyl group, an alkoxyalkyl group and an acyl group. These hydroxyl-protecting groups can be introduced and removed by a known method indicated in literatures (for example, T. W. Greene, P. G. M. Wuts, et al., Protective Groups in Organic Synthesis, Wiley-Interscience Publication). For example, a tert-butyldimethylsilyl group (TBDMS) may be introduced into the alcohol by treating the alcohol with a sililating agent such as tert-butyldimethylchlorosilane or tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of an acid scavenger. The amount of the sililating agent to be added may be generally about 1.0 to 1.5 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be, for example, dichloromethane, tetrahydrofuran, acetonitrile or pyridine. The inert medium may be preferably N,N-dimethylformamide. The amount of the inert medium to be used may be about 1 to 5 mL for 1 g of the alcohol. The acid scavenger may be triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine and the like. The acid scavenger may be, for example, preferably imidazole. The amount of the acid scavenger to be added may be generally about 1 to 3 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220 to 80xc2x0 C., particularly about 0xc2x0 C. to room temperature, for example, for 1 to 5 hours.
A benzyloxymethyl group (BOM) may be introduced into the alcohol by treating the alcohol with chloromethyl benzyl ether in the presence of an acid scavenger. The amount of chloromethyl benzyl ether to be added may be generally about 1.0 to 1.5 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be tetrahydrofuran, acetonitrile, N,N-dimethylformamide and the like. The inert medium may be preferably dichloromethane. The amount of the inert medium to be used may be about 1 to 5 mL for 1 g of the alcohol. The acid scavenger may be, for example, triethylamine, pyridine or N,N-dimethylaminopyridine. The acid scavenger may be preferably N,N-diisopropylethylamine. The amount of the acid scavenger to be added may be generally about 1 to 3 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220 to 80xc2x0 C., particularly about 0xc2x0 C. to room temperature, for example, for 1 to 5 hours.
In addition, an acetyl group (Ac) may be introduced into the alcohol by treating the alcohol with an acetylating agent such as acetic anhydride, acetyl chloride and the like in the presence of an acid scavenger. The amount of the acetylating agent to be added may be generally about 1 to 3 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out in an inert medium. The inert solvent may be, for example, preferably tetrahydrofuran, acetonitrile, dichloromethane or pyridine. The amount of the inert medium to be used may be about 1 to 5 mL for 1 g of the alcohol. The acid scavenger may be, for example, preferably triethylamine, N,N-diisopropylethylamine, pyridine or N,N-dimethylaminopyridine. The amount of the acid scavenger to be added may be generally about 1 to 3 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220 to 80xc2x0 C., particularly about 0xc2x0 C. to room temperature, for example, for 1 to 5 hours.
The hydroxyl-protecting group can be removed as follows. For example, a tert-butyldimethylsilyl group may be removed by treating a tert-butyldimethylsilyl ether with tetrabutylammonium fluoride. The amount of tetrabutylammonium fluoride to be added may be generally about 1 to 3 mol for 1 mol of the tert-butyldimethylsilyl ether. Generally, this reaction is preferably carried out in a medium such as tetrahydrofuran. The amount of the medium to be used may be generally about 1 to 5 mL for 1 g of the alcohol. Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220 to 60xc2x0 C., particularly about 0xc2x0 C. to room temperature, for example, for 1 to 5 hours. This reaction is preferably carried out in the presence of acetic acid. The amount of acetic acid to be added may be generally about 1 to 2 mol for 1 mol of the tert-butyldimethylsilyl ether.
A benzyloxymethyl group may be removed, for example, by hydrogenolysis reaction using a catalyst such as palladium/carbon or palladium hydroxide/carbon. The amount of the catalyst to be used may be generally about 5 to 20% by weight with respect to the benzyloxymethyl ether. Generally, this reaction is preferably carried out in a medium such as methanol, ethanol, tetrahydrofuran, acetic acid and the like. The amount of the medium to be used may be generally about 1 to 5 mL for 1 g of the benzyloxymethyl ether. Generally, this reaction is preferably carried out at a temperature of about xe2x88x9210 to 50xc2x0 C., particularly at room temperature, for example, for 3 to 10 hours.
An acetyl group may be removed by subjecting an acetic ester to hydrolysis reaction using a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like. The amount of the base to be added may be generally about 0.1 to 10 mol for 1 mol of the acetic ester. Generally, this reaction is preferably carried out in a medium such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane, or a water-mixed medium thereof. The amount of the medium to be used may be generally about 1 to 5 mL for 1 g of the acetic ester.
Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220 to 100xc2x0 C., particularly about 0 to 50xc2x0 C., for example, for 1 to 5 hours.
In accordance with the present invention, a compound having the hydroxyl group attached to the asymmetric carbon atom *1, which is derived from the reduction of the corresponding carbonyl group, can be used in the following reactions without protection of the hydroxyl group. It is preferred, however, that such a compound is used after being protected with a suitable protecting group as occasion requires.
The amino-protecting group can be removed by a known method indicated in literatures (for example, T. W. Greene, P. G. M. Wuts, et al., Protective Groups in Organic Synthesis, Wiley-Interscience Publication). For example, a benzyl group may be removed by hydrogenolysis reaction using a catalyst such as palladium/carbon or palladium hydroxide/carbon. The amount of the catalyst to be used may be generally about 5 to 20% by weight with respect to the protected amine. Generally, this reaction is preferably carried out in a medium such as methanol, ethanol, tetrahydrofuran, acetic acid and the like. The amount of the medium to be used may be generally about 1 to 5 mL for 1 g of the protected amine. Generally, this reaction is preferably carried out at a temperature of about xe2x88x9210 to 50xc2x0 C., particularly at room temperature, for example, for 3 to 10 hours. When R21 is a halogen atom, however, the amino-protecting group is removed by a known method indicated in the literatures (M. Koreeda et al., Journal of Organic Chemistry, 49, p. 2081 (1984) and S. Gubert et al., Synthesis, 4, p. 318 (1991)).
An acetyl group may be removed according to the acetic ester-hydrolyzing process using basic condition as set forth above. When an acyl group is used as the amino-protecting group, however, it may be preferred that this hydrolysis reaction is generally carried out at a temperature of room temperature to about 100xc2x0 C.
A tert-butoxycarbonyl group (Boc) may be removed by reacting the corresponding protected amine with a known mineral acid or Lewis acid. The known mineral acid or Lewis acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, aluminum chloride, bromotrimethylsilane, iodotrimethylsilane and the like, with hydrochloric acid being preferred. The amount of the mineral acid or Lewis acid to be added may generally vary from about the same molar amount with respect to the protected amine to a solvent amount with respect to the protected amine. This reaction can be carried out in a medium. However, this reaction may also be preferably carried out using the above acid as a medium. The medium may be a lower alcohol such as methanol, ethanol and n-propanol, 1,4-dioxane, tetrahydrofuran, acetonitrile, dichloromethane and the like, with methanol and ethanol being preferred. Generally, this reaction is preferably carried out at a temperature of about xe2x88x9230 to 100xc2x0 C., particularly about 0xc2x0 C. to room temperature, for example, for 1 to 10 hours.
The hydroxyl- and amino-protecting groups may be sequentially or simultaneously removed. For example, when R21 is a benzyloxy group, R3 is a benzyl group and R4 is a benzyl or benzyloxycarbonyl group respectively, they can be removed under the same reaction condition and are preferably simultaneously removed. When R21 is a benzyloxy group and R4 is a tert-butoxycarbonyl group respectively, they can be removed by sequential steps comprising, for example, the first removal of the tert-butoxycarbonyl group as R4 followed by the removal of the benzyloxy group as R21. The sequence of removal is not limit to the above and is preferably selected depending on the physical properties of the compound to be deprotected. The condition for removing each protecting group is as set forth above. In addition, these deprotection can be carried out with reference to the teachings of JP-A-9-249623.
Examples of a compound represented by the formula (1) include
2-[N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(3-methylsulfonylamino)phenylethanol;
2-[N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(4-hydroxy-3-methylsulfonylamino)phenylethanol;
2-[N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(4-bromo-3-methylsulfonylamino)phenylethanol;
2-[N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(4-chloro-3-methylsulfonylamino)phenylethanol; and
2-[N-[2-(6-hydroxy-9H-carbazol-2-yloxy)]ethyl]amino-1-(3-methylsulfonylamino)phenylethanol.
The most preferred examples are the above-mentioned compounds in the R-form.
The processes for the preparation of a compound represented by the formula (1) according to the present invention are illustrated in more detail in the followings.
[Preparing Process 1]
A compound of the formula (4) is condensed with a compound of the formula (12) to give a compound of the formula (3), which is then reduced to give an amino-alcohol of the formula (2). At the final step, the protecting groups are simultaneously or sequentially removed to give a compound of the formula (1).
A compound represented by the formula (4) is a known compound and can be synthesized by the method indicated in the literature (A. A. Larsen et al., J. Med. Chem., 10, p. 462 (1967), or C. Kaiser et al., J. Med. Chem., 7, p. 49 (1974)).
A compound represented by the formula (3), which is a novel compound and is relatively good in crystallinity, is characteristic of the present process as an important intermediate. The recrystallizing step can be carried out by a commonly applicable means, which may be preferably a means comprising dissolving a compound of the formula (3) in a lower alcohol such as methanol or ethanol, followed by cooling to allow the compound to crystallize.
A compound represented by the formula (3) can be obtained by reacting a compound of the formula (4) with a compound of the formula (12). The amount of the compound of the formula (12) to be added may be about 0.9 to 5 mol for 1 mol of the compound of the formula (4). Generally, this reaction is preferably carried out in an inert medium. The inert medium may be, for example, acetonitrile, acetone, methyl ethyl ketone, methanol, ethanol, tetrahydrofuran or dichloromethane, with tetrahydrofuran being preferred. The amount of the inert medium to be used may be generally about 1 to 100 mL for 1 g of the compound of the formula (4).
Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220xc2x0 C. to 100xc2x0 C., particularly about 0 to 50xc2x0 C., for example, for 3 to 10 hours. This reaction is also preferably carried out in the presence of a base as an acid scavenger. As the base, a tertiary amine or an inorganic base can be used. The tertiary amine may be, for example, triethylamine, N,N-diisopropylethylamine or N,N-dimethylaminopyridine. The inorganic base may be, for example, potassium carbonate or potassium hydrogen carbonate. The amount of the acid scavenger to be used may be generally 1 to 5 mol for 1 mol of the compound of the formula (4).
A compound represented by the formula (12) can be obtained by protecting a primary amine which is a known compound represented by the formula: 
(synthesized by the known method indicated in JP-A-9-249623) with a protecting group R4. That is, when R4 is a benzyl group, the protecting step can be carried out by reductive alkylation reaction with benzaldehyde, or by alkylation reaction with benzyl halide, benzyl sulfonate and the like. For example, the amount of benzaldehyde to be added according to the reductive alkylation reaction may be generally about 1 to 1.5 mol for 1 mol of the compound of the formula (12). Generally, this reaction is preferably carried out in a medium such as tetrahydrofuran, water, methanol or ethanol. Methanol may be most preferably used as the medium. The amount of the medium to be used may be generally about 10 to 100 mL for 1 g of the compound of the formula (12). Generally, this reaction is preferably carried out at room temperature, for example, for 3 to 10 hours. Further, it is also preferred that this reaction is generally carried out in the presence of a platinum group metal-comprising catalyst. The platinum group metal-comprising catalyst may be preferably platinum oxide. The amount of the platinum group metal-comprising catalyst to be used may be generally about 0.01 to 0.1 mol for 1 mol of the compound of the formula (12). This reaction is to be carried out under a hydrogen atmosphere. Generally, it may be preferably carried out at a pressure of about 1 to 10 atm, particularly preferably about 1 to 3 atm.
Alternatively, a compound represented by the formula (12) may be synthesized from a compound represented by Axe2x80x2xe2x80x94OH by a process consisting of 2 steps. That is, a compound of the formula (12) can be obtained by reacting a known compound of Axe2x80x2xe2x80x94OH with 1,2-dibromoethane to give the corresponding brominated compound, followed by reacting with an amine (NH2xe2x80x94R4)(in case that R4 is a substituted benzyl group).
The reaction between a compound represented by Axe2x80x2xe2x80x94OH and 1,2-dibromoethane may be carried out in an organic solvent, generally in the presence of a base at a temperature of room temperature to the reflux temperature of the thus selected solvent. The amount of 1,2-dibromoethane to be used is preferably 3 to 15 mol for 1 mol of the compound of Axe2x80x2xe2x80x94OH. The solvent may be dimethylformamide, dimethylacetamide, 2-butanone, acetonitrile, diglyme or tetrahydrofuran. The base may be potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, sodium hydride, sodium methoxide and the like, which is preferably used at an amount of 1 to 5 mol for 1 mol of the compound of Axe2x80x2xe2x80x94OH. The amount of the medium to be used is generally about 5 to 100 mL for 1 g of the compound of Axe2x80x2xe2x80x94OH. Generally, this reaction is preferably carried out at a temperature of 60 to 90xc2x0 C., for example, for 3 to 24 hours.
The reaction of the brominated compound with NH2xe2x80x94R4 may be carried out in a solvent or without solvent at a temperature of 60 to 100xc2x0 C. The amount of NH2xe2x80x94R4 to be used may be 2 to 10 mol for 1 mol of the brominated compound. The solvent may be dimethylformamide, dimethylacetamide, dimethylsulfoxide, 2-propanol and the like.
A compound represented by the formula (2) can be obtained by reducing a compound represented by the formula (3) with a known reducing agent. The reducing agent may be, for example, sodium borohydride, borane or diisobutylaluminum hydride. The reducing reaction may be preferably carried out with a metal hydride such as sodium borohydride, or with hydrogen in the presence of a platinum group metal-comprising catalyst such as palladium catalyst. The amount of sodium borohydride to be added may be generally about 1 to 3 mol for 1 mol of the compound of the formula (3). Generally, this reaction is preferably carried out in a lower alcohol. The lower alcohol may be, for example, methanol or i-propanol, and is preferably ethanol. The amount of the lower alcohol to be used may be generally about 1 to 5 mL for 1 g of the compound of the formula (3). However, when the solubility is insufficient, it may be preferred that tetrahydrofuran as a cosolvent is generally added in an amount of about 1 to 5 mL for 1 g of the compound of the formula (3). Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220 to 50xc2x0 C., particularly about 0xc2x0 C. to room temperature, for example, for 1 to 5 hours.
In addition, if an optical isomer of either R-form or S-form with respect to *1 of the formula (2) is to be obtained, it can be obtained by asymmetric reduction in the presence of an asymmetric reduction catalyst known from a variety of literatures (for example, Achiwa et al. Chem. Pharm., Bull., 43, p. 748 (1995) or Nozaki et al. J. Org. Chem., 59, pp. 3064-3076 (1994).
The method of Nozaki et al. is concerned with an asymmetric reduction with respect to 1,1-dimethylaminoacetone, in which method a cationic ruthenium-BINAP(2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl) complex of [RuI((S)-BINAP)(p-cymene)]+ Ixe2x88x92 is used, and this method may also be preferred for the present invention.
Further, WO 97/20789 and JP-A-9-157196 each teach a variety of processes for the preparation of an optically active alcohol from a ketone compound. Such processes use a metal complex comprising a transition metal with various ligands, more preferably, for example, a transition metal complex which may be represented by MXmLn wherein M represents a transition metal of the VIII group such as iron, cobalt, nickel, ruthenium, rhodium, iridium, osmium, palladium or platinum; X represents a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or an alkoxyl group; L represents a neutral ligand such as an aromatic compound or an olefin compound; m and n represent an integer. Ruthenium is a preferred transition metal to be contained in such transition metal complexes. When the neutral ligand is an aromatic compound, it may be a monocyclic aromatic compound. The aromatic compound may be substituted with various substituents such as a hydrogen atom, a saturated or unsaturated hydrocarbon group, an allyl group or a functional group containing heteroatom(s), at any positions of the aromatic compound, and the number of the substituents is not limited. The substituents may be specifically an alkyl group such as methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl, hexyl, heptyl and the like; a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; an unsaturated hydrocarbon group such as benzyl, vinyl, allyl and the like; or a functional group containing heteroatom(s) such as hydroxyl group, alkoxyl group, alkoxycarbonyl group and the like.
In addition, specific examples of metal complex include the followings.
[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]benzene ruthenium complex;
[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
[(R,R)-N-(o-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
[(R,R)-N-(2-mesitylenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
((R,R)-N-methanesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
((R,R)-N-benzenesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
[(R,R)-N-(p-fluorobenzenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
((R,R)-N-trifluoromethanesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
[(R,R)-N-(p-methoxybenzenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
((R,R)-N-methanesulfonyl-1,2-diphenylethylenediamine)mesitylene ruthenium complex;
[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]mesitylene ruthenium complex;
hydride-[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]benzene ruthenium complex;
hydride-[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
hydride-[(R,R)-N-(o-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
hydride-[(R,R)-N-(2-mesitylenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
hydride-((R,R)-N-methanesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
hydride-((R,R)-N-benzenesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
hydride-[(R,R)-N-(p-fluorobenzenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
hydride-((R,R)-N-trifluoromethanesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
hydride-[(R,R)-N-(p-methoxybenzenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
hydride-((R,R)-N-methanesulfonyl-1,2-diphenylethylenediamine)mesitylene ruthenium complex;
hydride-[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]mesitylene ruthenium complex;
chloro-[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]benzene ruthenium complex;
chloro-[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
chloro-[(R,R)-N-(o-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
chloro-[(R,R)-N-(2-mesitylenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
chloro-((R,R)-N-methanesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
chloro-((R,R)-N-benzenesulfonyl-1,2-diphenylethylenediamine)(p-cymene) ruthenium complex;
chloro-[(R,R)-N-(p-fluorobenzenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
chloro-((R,R)-N-trifluoromethanesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
chloro- [(R,R)-N-(p-methoxybenzenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex;
chloro-[(R,R)-N-methanesulfonyl-1,2-diphenylethylenediamine]mesitylene ruthenium complex; and
chloro-[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]mesitylene ruthenium complex.
Further, an asymmetric reduction using a catalyst is known, wherein the catalyst is obtained by reacting the following rhodium complex with the following chiral phosphine ligand. For example, [Rh(nbd)2]ClO4 (wherein nbd means norbornadiene), [Rh(nbd)Cl]2, [Rh(cod)Cl]2 (wherein cod means cycloocta-1,5-diene), and the like are known as a rhodium complex. Examples of chiral phosphine ligand include (2R,3R)-2,3-bis(diphenylphosphino)-bicyclo[2,2,1]hept-5-ene [abbr.: (R,R)-NORPHOS]; (R)-5,5xe2x80x2-dimethoxy-4,4xe2x80x2,6,6xe2x80x2-tetramethyl-2-diphenylphosphino-2xe2x80x2-dicyclohexylphosphino-1,1xe2x80x2-biphenyl [abbr.: (R)-MOC-BIMOP]; (R)-5,5xe2x80x2-dimethoxy-4,4xe2x80x2,6,6xe2x80x2-tetramethyl-2,2xe2x80x2-bis(dicyclohexylphosphino)-1,1xe2x80x2- biphenyl [abbr.: (R)-Cy-BIMOP]; (2S,3S)-1,4-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,3-(O-isopropylidene)-2,3-butanediol [abbr.: (S,S)-MOD-DIOP]; (2S,3S)-1,4-bis(diphenylphosphino)-2,3-(O-isopropylidene)-2,3-butanediol [abbr.: (S,S)-DIOP]; (2S,3S)-1-diphenylphosphino-4-dicyclohexylphosphino-2,3-(O-isopropylidene)-2,3-butanediol [abbr.: (S,S)-DIOCP]; (R)-1-[(S)-1xe2x80x2,2-bis(diphenylphosphino)ferrocenyl]ethanol [abbr.: (R)-(S)-BPPFOH]; (S)-1-[(S)-1xe2x80x2,2-bis(diphenylphosphino)ferrocenyl]ethanol [abbr.: (S)-(S)-BPPFOH]; (1S,2S)-1-diphenylphosphino-2-(diphenylphosphinomethyl)cyclopentane [abbr.: (S,S)-PPCP]; and (1S,2R)-1-dicyclohexylphosphino-2-(diphenylphosphinomethyl)cyclopentane [abbr.: (R,R)-CPCP].
When an asymmetric reduction according to the present invention is carried out in the presence of such a known catalyst, a suitable catalyst can be previously selected by checking the fact that the said reduction can appropriately proceed in the presence of the catalyst. However, such a checking may limit suitable catalysts, there is some possibility that appropriate catalysts to be selected is limited. Particularly preferred examples of the catalyst include those obtained by reacting a rhodium complex represented by the formula [Rh(cod)Cl]2 wherein cod means cycloocta-1,5-diene, with any one of chiral phosphine represented by the formula (16): 
or the formula (17): 
wherein Cy means a cyclohexyl group. That is, a hydrochloride compound of the formula (3) is reduced with hydrogen in the presence of the said complex [Rh(cod)Cl]2 and a chiral phosphine ligand represented by the formula either (16) or (17). These reactions may be carried out according to the literature (Achiwa et al., Chem. Pharm. Bull., 43, p 748 (1995)). For example, an optically active compound (amino-alcohol) represented by the formula (2) can be obtained by reducing a hydrochloride compound (ketoamine) of the formula (3) with hydrogen in the presence of a catalyst prepared from [Rh(cod)Cl]2, a chiral phosphine ligand represented by the formula (16) and a base. A chiral phosphine ligand represented by the formula (16) or (17) having the conformation (2R,4R) is preferably used, when an objective compound to be obtained by asymmetric reduction is in the R-form. The amount of [Rh(cod)Cl]2 to be added may be generally about 10xe2x88x925 to 10xe2x88x921 mol for 1 mol of the ketoamine hydrochloride. The amount of the chiral phosphine ligand represented by the formula (16) to be added may be generally about 2.6 mol for 1 mol of Rh. Examples of the base include N,N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium methoxide and potassium tert-butoxide. The base may be preferably triethylamine. The amount of the base to be added may be generally about 5xc3x9710xe2x88x923 mol for 1 mol of the ketoamine hydrochloride. Generally, this reaction may be preferably carried out under a hydrogen atmosphere at atmospheric pressure to about 50 atm, more preferably at atmospheric pressure to about 20 atm. It is generally preferred to carry out this reaction in a medium. Examples of the medium include toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethanol, n-propanol, i-propanol and water. The medium may be preferably methanol. The amount of the medium to be used may be generally about 5 to 30 mL for 5 mmol of the ketoamine hydrochloride. This reaction is generally carried out at a temperature of about 0 to 100xc2x0 C., preferably room temperature to about 50xc2x0 C., for example, preferably for 0.5 to 2 days.
As set forth above, the ketoamine in the form of hydrochloride is more preferably used than its free form as a reactant in the present asymmetrically reducing process using a catalyst prepared from a rhodium complex.
Next, a compound of the formula (1) can be obtained by simultaneously or sequentially removing the protecting groups according to the method as set forth above.
In each step of the synthesizing route set forth above, the produced material is preferably purified by a known purifying means, such as column chromatography. However, the intermediate products such as a novel compound represented by the formula (3) are relatively good in crystallinity and can be used in the following reaction step after being subjected to a simple recrystallizing treatment without hard labor. Therefore, the present process, which can save cost and complicated process, is a preferred process. In addition, the present process is also preferred in that each step results in good yield and that the number of steps is relatively few.
[Preparing Process 2]
A compound of the above-mentioned general formula (3) may be synthesized by either process as set forth below. That is, a compound of the formula (3) can be obtained by condensing a compound of the formula (4) with a compound of the formula (14) to give a compound of the formula (6); and converting its hydroxyl group into a leaving group B3 to give a compound of the formula (5), which is then condensed with a compound represented by Axe2x80x2xe2x80x94OH.
The condensation of a compound of the formula (4) with a compound of the formula (14) can be carried out under the same reaction conditions with those of the reaction of a compound of the formula (4) with a compound of the formula (12) according to the Preparing Process 1 as set forth above. In this connection, R4 in the formula (14) and R4 in the formula (12), which are common in that they are an amino-protecting group, do not necessarily mean the same group and may be different from each other.
A compound represented by the formula (6) obtained by the condensation of a compound of the formula (4) with a compound of the formula (14) is novel and is a preferred intermediate. The compound does not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
Among compounds represented by the formula (14), which can be synthesized by the same reaction conditions with those of Referential Examples of the present text of specification, a compound of the formula (14) in which R4 is a benzyl group is commercially available (mfd. by TOKYO KASEI KOGYO) and is particularly preferred.
A compound represented by the formula (5) can be obtained by converting the hydroxyl group (the primary hydroxyl group) of the side-chain of a compound of the formula (6) to a leaving group B3. The conversion into a leaving group B3 may be carried by halogenation with a known halogenating agent such as hydrogen bromide/acetic acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, thionyl bromide, bromine/triphenylphosphine, carbon tetrachloride/triphenylphosphine, carbon tetrabromide/triphenylphosphine, N-bromosuccinimide/triphenylphosphine and the like, or by sulfonic esterification with a sulfonyl chloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride and the like. For example, a compound of the formula (5) in which B3 is bromine may be obtained by treating a compound of the formula (6) with about 1- to 10-fold moles of phosphorus tribromide. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be, for example, 1,2-dichloroethane or carbon tetrachloride, and is preferably dichloromethane. The amount of the inert medium to be used may be generally about 1 to 10 mL for 1 g of the compound of the formula (6). This reaction is generally carried out at a temperature of about xe2x88x9230 to 100xc2x0 C., particularly about 0 to 50xc2x0 C., for example, preferably for 1 to 5 hours. In addition, a methanesulfonate ester may be generally obtained by treating a compound of the formula (6) with about 1- to 3-fold moles of methanesulfonic chloride. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be, for example, dichloromethane, tetrahydrofuran or toluene, and is preferably pyridine. The amount of the inert medium to be used may be generally about 1 to 10 mL for 1 g of the compound of the formula (6). This reaction is generally carried out at a temperature of about xe2x88x9220 to 100xc2x0 C., preferably about 0 to 50xc2x0 C., for example, preferably for about 1 to 5 hours. This reaction may be also preferably carried out in the presence of a tertiary amine such as triethylamine, N,N-diisopropylethylamine, N,N-dimethylaminopyridine and the like. The amount of the tertiary amine to be used may be about 1- to 5-fold moles.
As obtained sulfonate ester compound may be directly subjected to the following condensation reaction with a compound represented by Axe2x80x2xe2x80x94OH, or may be first halogenated with a halogenating agent such as sodium chloride, sodium bromide, sodium iodide, potassium bromide or potassium iodide by a known method (for example, Org. Syn. Coll. Vol., 4, p. 753 (1963)) followed by condensation with a compound represented by Axe2x80x2xe2x80x94OH. Generally, the iodide may be obtained by treating the corresponding sulfonate ester with about 1- to 10-fold moles of sodium iodide. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be, for example, 2-butanone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or sulfolane, and is preferably acetone. The amount of the inert medium to be used may be generally about 1 to 10 mL for 1 g of the sulfonate ester. This reaction is generally carried out at a temperature of about 0 to 150xc2x0 C., preferably about room temperature to about 100xc2x0 C., for example, preferably for 3 to 10 hours.
Generally, the condensation reaction of a compound of the formula (5) with a compound represented by Axe2x80x2xe2x80x94OH is preferably carried out by reacting 1 to 5 mol of the compound of Axe2x80x2xe2x80x94OH for 1 mol of the compound of the formula (5) in a basic condition. The basic condition preferably comprises treatment with an alkali such as potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride and potassium tert-butoxide. In this basic condition the compound of Axe2x80x2xe2x80x94OH is formed into the metal alkoxide by each alkali. The amount of the metal alkoxide to be used may be generally about 1 to 3 mol for 1 mol of the halide or sulfonic ester. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be, for example, acetone, 2-butanone, tetrahydrofuran, N,N-dimethylacetamide, dimethylsulfoxide or sulfolane, and is preferably N,N-dimethylformamide. The amount of the inert medium to be used may be generally about 1 to 10 mL for 1 g of the sulfonic ester. Generally, this reaction is preferably carried out at a temperature of room temperature to about 100xc2x0 C., for example, for 3 to 10 hours.
In addition, a ketoamine represented by the formula (3) may be obtained by directly condensing a compound of the formula (6) with a compound represented by Axe2x80x2xe2x80x94OH according to Mitsunobu reaction. The reaction can be carried out in accordance with the method indicated in literatures (for example, Mitsunobu et al. Journal of Organic Chemistry, 50, p. 3095 (1985)). For example, a compound of the formula (6) may be reacted with 1- to 2-fold moles of a compound of Axe2x80x2xe2x80x94OH in the presence of 1- to 2-fold moles of a condensing agent prepared from a trivalent organophosphorus compound, such as triphenylphosphine, triethylphosphine, triethylphosphine and the like, and an azo compound such as diethyl azodicarboxylate (DEAD), N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl-azodicarboxamide (TMAD), 1,1-(azodicarbonyl)dipiperidine (ADDP), cyanomethylenetributyl phosphorane (CMBP) or cyanomethylenetrimethyl phosphorane (CMMP), phosphorane and the like. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be benzene or toluene, and is preferably tetrahydrofuran. The amount of the inert medium to be used may be generally about 1 to 10 mL for 1 g of the compound of the formula (6). This reaction is generally carried out at a temperature of about 0 to 100xc2x0 C., preferably about 0 to 50xc2x0 C., most preferably room temperature to 50xc2x0 C., for example, preferably for 3 to 10 hours.
A compound represented by Axe2x80x2xe2x80x94OH can be obtained by the methods disclosed in JP-A-9-249623 (WO 97/25311) and WO 99/01431. However, 2-hydroxycarbazole is commercially available (mfd. by Aldrich) and such commercially available products are easily used and preferred.
The thus obtained compound of the formula (3) can be subjected to the following synthesizing steps in accordance with the same conditions with those of the Preparing Process 1 as set forth above to give each of a compound of the formula (2) and a compound of the formula (1).
In each step of the synthesizing route set forth above, the produced material is preferably purified by a known purifying means, such as column chromatography. However, the intermediate products such as a novel compound represented by the formula (3) are relatively good in crystallinity and can be used in the following reaction step after being subjected to a simple recrystallizing treatment without hard labor. Therefore, the present process, which can save cost and labor, is a preferred process. In addition, the present process is also preferred in that each step results in good yield and that the number of steps is relatively few.
[Preparing Process 3]
A compound of the above-mentioned general formula (2) may be also synthesized by a process set forth below. That is, an amino-alcohol represented by the formula (2) can be obtained by reducing the carbonyl group of a compound of the formula (5) to give a compound of the formula (7), followed by condensation with a compound represented by Axe2x80x2xe2x80x94OH.
The reaction for reducing or asymmetrically reducing a compound of the formula (5) can be carried out under the same reaction conditions with those of the process for synthesizing a compound of the formula (2) from a compound of the formula (3) set forth above (Preparing Process 1).
The condensation reaction of a compound of the formula (7) with a compound represented by Axe2x80x2xe2x80x94OH can be carried out under the same reaction conditions with those of the process for synthesizing a compound of the formula (3) from a compound of the formula (5) as set forth above (Preparing Process 2). For example, the condensation reaction is preferably carried out in a basic condition.
The thus obtained compound of the formula (2) can be subjected to the following synthesizing steps in accordance with the same conditions with those of the Preparing Process 1 set forth above to give a compound of the formula (1).
In each step of the synthesizing route set forth above, the produced material is preferably purified by a known purifying means, such as column chromatography. However, the intermediate products such as a novel compound represented by the formula (6) do not necessarily need a purifying step and can be used in the following reaction step after being subjected to a simple treatment, such as a recrystallizing treatment. Therefore, the present process, which can save cost and labor, is a preferred process. In addition, the present process is also preferred in that each step results in good yield and that the number of steps is relatively few.
[Preparing Process 4]
A compound of the formula (2) may be also synthesized by either process set forth below. That is, a compound represented by the above-mentioned general formula (6) is reduced (or asymmetrically reduced) to give a compound of the formula (8). Next, (i) the primary hydroxyl group of the compound of the formula (8) can be converted into a leaving group B3 to give a compound of the formula (7), which can be then condensed with a compound represented by Axe2x80x2xe2x80x94OH in accordance with the Preparing Process 3 set forth above to give a compound of the formula (2).
Alternatively, (ii) the compound of the formula (8) can be subjected to Mitsunobu reaction with a compound represented by Axe2x80x2xe2x80x94OH to give a compound of the formula (2).
The reaction for reducing or asymmetrically reducing a compound of the formula (6) can be carried out under the same reaction conditions with those of the process for synthesizing a compound of the formula (2) from a compound of the formula (3) as set forth above (Preparing Process 1).
A compound represented by the formula (8) obtained by the reduction (or asymmetric reduction) of a compound of the formula (6) is novel and is a preferred intermediate. The compound does not necessarily need a purifying step and may be used in the following reaction step after being subjected to a simple treatment, such as a recrystallizing treatment. Therefore, the present process using the said compound can save cost and labor.
A compound represented by the formula (7) can be obtained by treating the primary hydroxyl group of a compound of the formula (8) in accordance with the same methods with those for preparing a compound of the formula (5) from a compound of the formula (6) as set forth above (Preparing Process 2).
The step of directly condensing a compound of the formula (8) with a compound represented by Axe2x80x2xe2x80x94OH according to Mitsunobu reaction to give a compound of the formula (2), can be carried out by reacting a compound of the formula (8) with a compound represented by Axe2x80x2xe2x80x94OH in the presence of a trivalent organophosphorus compound and an azo compound or phosphorane as a condensing agent as set forth above (Preparing Process 2).
The thus obtained compound of the formula (2) can be treated under the same conditions with those of the Preparing Process 1 as set forth above to give a compound of the formula (1).
In each step of the synthesizing route set forth above, the produced material is preferably purified by a known purifying means, such as column chromatography. However, compounds represented by the formulae (6) and (8), which are novel compounds, do not necessarily need a purifying step and may be used in the following reaction step after being subjected to a simple treatment, such as a recrystallizing treatment. Therefore, these compounds are preferred intermediates which can save cost and labor. In addition, the present process is also preferred in that each step results in good yield and that the number of steps is relatively few.
[Preparing Process 5]
A compound of the formula (4) is condensed with a compound of the formula (13) to give a compound of the formula (11), the carbonyl group of which is then reduced to give a compound of the formula (10). After the amino groups are protected, the compound of the formula (10) is condensed with a compound represented by Axe2x80x2xe2x80x94OH to give a compound of the formula (9). The amino-protecting groups can be simultaneously or sequentially removed to give a compound of the formula (1).
A compound of the formula (11) can be obtained by treating a compound of the formula (4) with a compound of the formula (13). The amount of the compound of the formula (13) to be added may be generally about 1 to 5 mol for 1 mol of the compound of the formula (4). Generally, this reaction is preferably carried out in the presence of an acid scavenger. The acid scavenger may be, for example, a tertiary amine such as triethylamine or N,N-diisopropylethylamine, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, and is preferably sodium hydroxide. The amount of the acid scavenger to be added may be generally about 2 to 10 mol for 1 mol of the compound of the formula (4). Generally, this reaction is preferably carried out in a lower alcohol such as methanol, ethanol or i-propanol, tetrahydrofuran or 1,4-dioxane, or a water-mixed medium thereof. The amount of the medium to be used is generally about 1 to 5 mL for 1 g of the compound of the formula (4). Generally, this reaction is preferably carried out at a temperature of about 0 to 100xc2x0 C., particularly about 0 to 50xc2x0 C., for example, preferably for 3 to 10 hours.
A compound of the formula (13) in which B1 and B2 are chlorine or bromine is commercially available (mfd. by TOKYO KASEI KOGYO) and such commercially available products are easily used and preferred.
The reaction for reducing or asymmetrically reducing the carbonyl group of a compound of the formula (11) can be carried out under the same reaction conditions with those of the process for synthesizing a compound of the formula (2) from a compound of the formula (3) as set forth above (Preparing Process 1).
The amino group of a compound of the formula (10) can be protected with a protecting group R5 in accordance with a known method. For example, when R5 is a tert-butoxycarbonyl group, a compound of the formula (10) in which the amino group is protected with R5 can be obtained by treating the compound with di-tert-butyl dicarbonate in the presence of an acid scavenger. The acid scavenger may be preferably triethylamine, N,N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and the like. Generally, the amount of the acid scavenger to be added may be preferably about 1 to 3 mol for 1 mol of the compound (amino-alcohol hydrochloride) of the formula (10). Generally, this reaction is preferably carried out in a medium. The medium may be preferably a lower alcohol such as methanol, ethanol, n-propanol, i-propanol or tert-butanol, 1,4-dioxane or tetrahydrofuran, or a water-mixed medium thereof. The amount of the medium to be used is generally about 1 to 10 mL for 1 g of the amino-alcohol hydrochloride of the formula (10). Generally, this reaction is preferably carried out at a temperature of about xe2x88x9220 to 80xc2x0 C., particularly about 0 to 50xc2x0 C., most preferably about 0xc2x0 C. to room temperature, for example, preferably for 1 to 10 hours.
The amino-protecting groups of a compound of the formula (9) can be simultaneously or sequentially removed in accordance with a known method to give a compound of the formula (1).
In each step of the synthesizing route set forth above, the produced material is preferably purified by a known purifying means, such as column chromatography. However, each intermediate, particularly, a compound of the formula (11), which is included within the formula (18), and a compound of the formula (10), which is included within the formula (19), do not necessarily need a purifying step and may be used in the following reaction step after being subjected to a simple treatment, such as a recrystallizing treatment. The present process, which can save cost and labor, is a preferred process. In addition, the present process is also preferred in that each step results in good yield and that the number of steps is relatively few.
The step for asymmetrically reducing a carbonyl group according to Preparing Processes 1 to 5 set forth above, is characteristic of the present invention and is a particularly preferred step in each Preparing Process.
Preferred intermediates to be used in the preparing processes of the present invention include compounds represented by the following general formula (18) and salts thereof: 
wherein R1 represents a lower alkyl group or a benzyl group; R21 represents a hydrogen atom, a halogen atom, a hydroxyl group or a protected hydroxyl group; R3 represents an amino-protecting group or a hydrogen atom; R4 represents an amino-protecting group or a hydrogen atom; and B represents a hydroxyl group or a leaving group. The aforementioned general formulae (5), (6) and (11) are included within the formula (18). Compounds of the formula (18) are preferred compounds which are good in crystallinity.
The other preferred intermediates include compounds represented by the following general formula (19) and salts thereof: 
wherein R1 represents a lower alkyl group or a benzyl group; R21 represents a hydrogen atom, a halogen atom, a hydroxyl group or a protected hydroxyl group; R3 represents a hydrogen atom or an amino-protecting group; R4 represents an amino-protecting group or a hydrogen atom; B represents a hydroxyl group or a leaving group; and *1 represents an asymmetric carbon atom. The aforementioned general formulae (7), (8) and (10) are included within the formula (19).
As set forth above, a compound of the formula (1) in which R6 is a hydrogen atom can exist in the two different optically active substances. The processes described herein can provide a racemic mixture and also an optical isomer as occasion requires. The reactions set forth above should not alter the relating stereochemistry.
When R6 is a hydrogen atom, a mixture of two optical isomers with respect to *1 may be obtained. The mixture can be resolved into the optical isomers as their acid addition salts with an optically active acid such as camphorsulfonic acid, mandelic acid or substituted mandelic acid by a suitable method such as fractional crystallization. Such a fractional crystallization may be carried out using a suitable solvent, preferably a lower alcohol, such as methanol, ethanol, i-propanol or a mixture thereof. Each pair of enantiomers can be resolved into pure isomers by formation of diastereomeric salt, chromatography using an optically active column, or other means. When one of starting materials is optically active, the thus obtained mixture of diastereomers can be resolved into pure isomers by the above-mentioned means. Not only a compound of the formula (1) but also an intermediate amino-alcohol (2), (7), (8), (9) or (10) each obtained in the intermediate steps of the Preparing Processes 1 to 5 set forth above can be subjected to the said resolution. Optical resolution and purification of the present compounds can provide a preferred medicine which comprises a single isomer having higher activities and thereby has improved efficacy with little side effect.
Salts of a compound of the formula (1), (2), (3), (5), (6), (7), (8), (9), (10), (11), (18) or (19) according to the present invention may be a known salt, and examples thereof include hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate and methanesulfonate, and acid addition salts with an optically active acid such as camphorsulfonic acid, mandelic acid or substituted mandelic acid. Among them, pharmaceutically acceptable salts are particularly preferred. When a compound of the formula (1), (2), (3), (5), (6), (7), (8), (9), (10), (11), (18) or (19) is converted into its salt, an acid addition salt of the compound can be obtained by dissolving the compound in an alcohol such as methanol or ethanol, to which the equivalent amount to several times amount of the acid is then added. The acid to be used may be a pharmaceutically acceptable mineral or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogensulfate, dihydrogen phosphate, citric acid, maleic acid, tartaric acid, fumaric acid, gluconic acid, methanesulfonic acid and the like.
This specification includes part or all of the contents as disclosed in the specification of Japanese Patent Application No. 11-83917.